1. Field of the Invention
This invention relates to the microencapsulation of adjuvants for use in therapeutic or prophylactic vaccine formulations.
2. Description of the Background and Related Art
The instant invention provides for the delivery of an adjuvant or adjuvants to a host in a microsphere format. The adjuvant or adjuvants can be delivered concomitantly with an antigen packaged within the same microsphere or in some other delivery format; alternatively, an antigen can be provided before or after the adjuvant-containing microspheres, or be packaged independently in microspheres.
The encapsulated adjuvant of the invention may be used in traditional immunization protocols typically requiring multiple exposures of the patient to an antigen, usually by injections of a vaccine formulation at intervals of weeks or months. In addition, the encapsulated adjuvant of the invention may be delivered to the patient in a formulation which releases the antigen and/or adjuvant in bursts spaced days to months apart, thereby reducing the need for multiple injections. The initial burst of antigen and/or adjuvant can be augmented by the addition of soluble antigen and/or adjuvant to the vaccine formulation. Mixtures of microspheres which release the antigen and/or adjuvant in a pulsatile manner with microspheres which release the antigen and/or adjuvant continuously can also be used.
Different antigens can be combined in the formulation, either within the same microspheres or as a mixture of microspheres, to provide a multivalent or multitarget vaccine. Adjuvants may also be combined, either within the same microspheres or as a mixture of microspheres, to provide an additive or synergistic effect. Furthermore, as microspheres can be designed to release a second burst of antigen and/or adjuvant ("autoboost") when desired, a single vaccine preparation can be designed so as to mix populations of microspheres which release their bursts of antigens and/or adjuvants at multiple prescribed intervals when such multiple challenges with antigen and/or adjuvant are desired.
Preferred adjuvants for use in the compositions and methods of the instant invention include saponins and their derivatives. For example, U.S. Pat. No. 5,057,540 discloses the uses of Quillaja saponins, a mixture of triterpene glycosides extracted from the bark of the tree Quillaja saponaria, as immune adjuvants. Saponins can be isolated from other plants, such as soybeans (U.S. Pat. No. 4,524,067). White et al. (Immunology of Proteins and Peptides VI, ed. M. Z. Atassi, Plenum Press, N.Y., 1991) disclose the use of QS21 as an adjuvant for a T-independent antigen. Wu et al. (J. Immunol. 148:1519-1525, 1992) disclose the use of QS21 as an adjuvant for the HIV-1 envelop protein gp160 in mice. Newman et al. (AIDS Research and Human Retroviruses 8:1413-1418, 1992) disclose the use of QS21 as an adjuvant for the HIV-1 envelop protein Gp160 in rhesus macaques. Kensil et al. (J. Am. Vet. Med. Assoc. 199:1423-1427, 1991) disclose the use of QS21 as an adjuvant for the feline leukemia virus subgroup A gp70 protein.
Polymer matrices for forming microspheres are also described in the literature. For example, Chang et al. (Bioengineering 1:25-32, 1976) disclose semipermeable microspheres containing enzymes, hormones, vaccines, and other biologicals. U.S. Pat. No. 5,075,109 discloses a method of potentiating an immune response by administering a mixture of at least two populations of microspheres containing bioactive agents such that one of the microsphere populations is sized between about 1 to 10 .mu.m. U.S. Pat. No. 4,293,539 discloses a controlled release formulation of an active ingredient in a copolymer derived from about 60 to 95 weight percent lactic acid and about 40 to about 4 weight percent glycolic acid. U.S. Pat. No. 4,919,929 discloses the administration of an antigenic substance in a shaped structure of a biocompatible matrix material. U.S. Pat. No. 4,767,628 discloses composition comprising an active, acid stable polypeptide and a polylactide, which when placed in an aqueous physiological environment release the polypeptide at an approximately constant rate in an essentially monophasic manner. U.S. Pat. No. 4,962,091 discloses a microsuspension of water soluble macromolecular polypeptides in a polylactide matrix. U.S. Pat. Nos. 4,849,228 and 4,728,721 disclose a biodegradable, high molecular weight polymer characterized in that the content of water-soluble low molecular weight compounds, as calculated on the assumption that such compounds are monobasic acids, is less than 0.01 mole per 100 grams of high molecular weight polymer. U.S. Pat. Nos. 4,902,515 and 4,719,246 disclose polylactide compositions containing segments of poly(R-lactide) interlocked with segments of poly(S-lactide). U.S. Pat. No. 4,990,336 discloses a multiphasic sustained release system comprising allergen extract encapsulated in microspheres of bioerodible encapsulating polymer which permits a sustained, multiphasic release of the allergen. This system includes a first portion of allergen extract that upon injection is capable of being released in a manner whereby initial allergenicity is minimized to producing a mild local reaction similar to that normally observed with low doses of conventional allergen administration, and secondary portions of allergen extract that provide a substantially higher level of allergen extract in doses that could provide a serious reaction in the patient, but for the release of the first portion of allergen extract. U.S. Pat. No. 4,897,268 discloses a microcapsule delivery system wherein the ingredients are encapsulated in biodegradable copolymer excipients of varying mole ratios, such that delivery of the ingredients occurs at a constant rate over a prolonged period of time.
Various water-in-oil emulsions are described in the literature. Thus, for example, U.S. Pat. Nos. 4,917,893 and 4,652,441 disclose a microcapsule produced by preparing a water-in-oil emulsion comprising an inner aqueous layer containing a water-soluble drug, a drug-retaining substance, and an oil layer containing a polymer substance; the inner or aqueous layer is thickened or solidified to a viscosity of not lower than about 5000 centipoises. The resulting emulsion is subjected to in-water drying. U.S. Pat. No. 4,954,298 discloses the production of microcapsules by preparing a water-in-oil emulsion composed of a water-soluble drug-containing solution as the inner aqueous phase and a polymer-containing solution as the oil phase, dispersing the emulsion in an aqueous phase and subjected the resulting water-in-oil-in-water emulsion to an in-water drying, wherein the viscosity of the water-in-oil emulsion used in preparing the water-in-oil-in-water emulsion is adjusted to about 150 to about 10,000 centipoises.
Accordingly, it is an object of the invention to provide a microencapsulated adjuvant formulation for use in immunization of a patient against an antigen of interest.
This object and other objects will become apparent to those of ordinary skill in the art.